P2y(2) Receptor Activation Decreases Blood Pressure And Increases Renal Na+ Excretion

Rieg T, Gerasimova M, Boyer JL, Insel PA, Vallon V. P2Y(2) receptor activation decreases blood pressure and increases renal Na+ excretion. Am J Physiol Regul Integr Comp Physiol 301: R510-R518, 2011. First published May 25, 2011; doi:10.1152/ajpregu.00148.2011.-ATP and UTP are endogenous agonists of P2Y(2/4) receptors. To define the in vivo effects of P2Y(2) receptor activation on blood pressure and urinary excretion, we compared the response to INS45973, a P2Y(2/4) receptor agonist and UTP analog, in wild-type (WT) and P2Y(2) receptor knockout (P2Y(2)-/-) mice. INS45973 was administered intravenously as a bolus injection or continuous infusion to determine effects on blood pressure and renal function, respectively. Within seconds, bolus application of INS45973 (0.1 to 3 mg/kg body wt) dose-dependently decreased blood pressure in WT (maximum response -35 +/- 2 mmHg) and to a similar extent in endothelial nitric oxide synthase knockout mice. By contrast, blood pressure increased in P2Y(2)-/-(maximum response +18 +/- 1 mmHg) but returned to basal levels within 60 s. Continuous infusion of INS45973 (25 to 750 mu g.min(-1).kg(-1) body wt) dose-dependently increased urinary excretion of Na+ in WT (maximum response +46 +/- 15%) but reduced Na+ excretion in P2Y(2)-/- (maximum responses of -45 +/- 15%) mice. In renal clearance experiments, INS45973 did not affect glomerular filtration rate but lowered blood pressure and increased fractional excretion of fluid, Na+, and K+ in WT relative to P2Y(2)-/- mice. The blood pressure responses to INS45973 are consistent with P2Y(2) receptor-mediated NO-independent vasodilation and implicate responses to endothelium-derived hyperpolarizing factor, and P2Y(2) receptor-independent vasoconstriction, probably via activation of P2Y(4) receptors on smooth muscle. Systemic activation of P2Y(2) receptors thus lowers blood pressure and inhibits renal Na+ reabsorption, effects suggesting the potential utility of P2Y(2) agonism in the treatment of hypertension.